Molecular interaction between the voltage-dependent anion channel 2 and its agonist efsevin

• Applicant: Privatdozent Dr. Johann Schredelseker, Ph.D.
• Subject Area: Pharmacology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280381528

Cardiovascular diseases still dominate the statistics of mortality and health-care expenses worldwide. Despite these alarming facts current treatment options for arrhythmia and heart failure are limited and most current drugs, like antiarrhythmics and positive inotropic substances, display major side effect. The development of novel therapeutic strategies for the treatment of cardiovascular disease is thus a major pre-clinical endeavor of our time. We have recently identified an important role of mitochondria for regulation of cardiac rhythmicity and contractility. Pharmacological activation of the outer mitochondrial membrane voltage-dependent anion channel 2 (VDAC2) by the newly synthesized compound efsevin enhances mitochondrial calcium uptake and thereby restricts arrhythmogenic events in zebrafish hearts and isolated murine cardiomyocytes of a cardiac arrhythmia model. However the molecular nature of the efsevin-VDAC2 interaction remains elusive. This proposal seeks to investigate this interaction on a biochemical and biophysical level. Using purified VDAC2 protein incorporated into planar lipid bilayers we will investigate biophysical changes in gating behavior of the channel upon efsevin binding. This will deepen our understanding of the mechanism of drug action and will be a crucial step in the exploration of VDAC2 as a drug target. Furthermore, we will determine binding efficiency of efsevin and identify the binding site of efsevin on the VDAC2 channel protein. This will pave the way for structure guided design of optimized compounds. Finally, we will identify more potent derivatives of efsevin in a derivative screen and test those for their therapeutic potential. Success of this project will be an important step towards the establishment of a novel pharmacological target for the treatment of cardiovascular diseases. By selectively targeting intracellular target structures these agents are expected not to influence the cardiac action potential and thus to display less side effects compared to common actual drugs.

• DFG Programme: Research Grants